Acetazolamide Mitigates Opioid-Associated Sleep-Disordered Breathing

Rationale: Chronic prescription opioid use can exert ventilatory depression and increase loop gain to induce sleep disordered breathing (SDB). Alternative therapies to mitigate opioid-associated SDB are needed. Objective: We sought to examine whether oral acetazolamide (ACZ) will reduce SDB in opioid-associated SDB by reductions in plant and/or by increasing cerebrovascular responsiveness to CO2 (CCR) Methods: Nine adults with opioid-associated SDB were randomized to receive oral ACZ or placebo, in crossover fashion, for 6 days, with multiple measurements of awake CCR to hypercapnia on day 4, followed by measurements of apneic threshold, plant and controller gains (components of loop gain), using noninvasive mechanical ventilation during NREM sleep, and subsequent overnight polysomnography while still on the drug. Serum opioid and serum total CO₂ levels confirmed use of opioid drug and ACZ, respectively. Measurements and Main Results: Compared with placebo, ACZ significantly reduced SDB severity (apnea-hypopnea index, 25.2±8.3/hour vs.32.2±8.2/hour, p=0.03; central apnea-hypopnea index 0.9±0.3/hour vs. 5.0±1.1/hour, p=0.006, i.e. reduced 22% and 82%, respectively, with increased oxygen saturations). The reduction in SDB severity was accompanied with a significant reduction in plant gain with ACZ vs. placebo (4.0±0.7 mmHg vs.6.6±0.6 mmHg/L/min, p<0.001), driven by ACZ-induced metabolic acidosis leading to increased eupneic minute ventilation (10.0±1.4 L/min vs. 6.8±0.5 L/min, p=0.04), and reduced eupneic end-tidal CO₂ (33.1±1.2 mmHg vs. 41.6±1.1 mmHg, p<0.001). In contrast, the controller gain and CCR were unchanged with ACZ vs. placebo. Conclusions: Acetazolamide significantly mitigates opioid-associated sleep disordered breathing via reduction in plant gain but without alterations in ventilatory chemoresponsiveness or cerebrovascular responsiveness.